For patients with brain tumors, systemic delivery of therapeutics is usually associated with systemic side effects while achieving only marginal therapeutic concentrations in the central nervous system (CNS), and thus the efficacy of systemic treatment is limited. The observed lack of efficacy is primarily due to poor penetration of therapeutic agents across the blood-brain barrier. Although the blood-brain barrier may be disrupted at the core of the tumor allowing systemically-delivered chemotherapy agents access to the mostly inactive center of the tumor, the barrier typically remains intact at the growing tumor margin where the agent is needed most.
One approach to circumventing the blood brain barrier is direct infusion of therapeutic agents into the CNS. However, agents infused directly into the brain distribute poorly by diffusion. High concentration gradients are required to move even small molecule drugs millimeters from the infusion site, and such concentrations are often neurotoxic. A developing strategy to overcome this problem is a direct intracerebral infusion approach called convection-enhanced delivery (CED). CED employs positive pressure to generate a local pressure gradient for distributing agents, including therapeutic macromolecules, in the extracellular space. (Bobo, R. H., et al. (1994) Proc. Natl. Acad. Sci. USA 91:2076-80; Chen, M. Y., et al. (1999) J. Neurosurg. 90:315 20). CED provides reproducible distribution within a given target tissue and can produce homogeneous drug concentrations throughout the volume of distribution (Vd) (Croteau et al., 2005; Lonser et al., 2002).
Chemotherapeutic agents delivered locally by CED have produced favorable therapeutic outcomes (Bruce et al., 2000; Degen et al., 2003; Kaiser et al. 2000). However, most cytotoxic agents delivered directly to the nervous system have the capacity to damage healthy cells. Accordingly, good candidates for CED administration into brain tumors must have the highest possible therapeutic index against tumor cells in comparison with healthy neuronal cells. While liposomal drug delivery offers potential for avoiding the high peak drug concentrations that are often associated with pronounced toxicity, and preclinical studies of liposome-encapsulated camptothecin drugs given via CED have shown some improvement in the sustained release of the drug (Moog et al, 2002; Saito et al, 2006; Nobel et al, 2006), the use of PEGylated liposomes was deemed essential to mask tissue binding site interactions and thereby increase tissue distribution volume. (Saito et al, 2006).
Despite the success of PEGylation in overcoming liposome/tissue interactions, it has recently been demonstrated that PEGylated liposomes may generate unwanted and potentially life-threatening immune responses (Szebeni et al. (2007) J. Liposome Res. 17:107-117; Ishida and Kiwada (2008) Int. J. Pharm. 354:56-62 Epub Nov. 9, 2007). In addition to accelerated blood clearance when administered into the same subject twice, PEGylated liposomes may cause non-IgE-mediated hypersensitivity reactions, which include symptoms of cardiopulmonary distress (e.g., dyspnea, tachypnea, tachycardia, chest pain, hypertension, and hypotension) (Ishida and Kiwada (2008), supra; Moghimi et al. (2006) FASEB J. 20:2591-3 Epub Oct. 25, 2006).
What is needed, therefore, is an improved liposomal drug formulation for convection-enhanced delivery that provides increased tissue distribution volume, but avoids the problematic immunogencity associated with PEGylation.